Injectable combination of adrenergic receptor agonists with fillers, for decreasing skin reactions due to injection

ABSTRACT

The present invention concerns an injectable composition comprising a filler or a botulinum toxin and an adrenergic receptor agonist, and its use for diminishing, decreasing or avoiding skin reactions due to injection, specially redness, ecchymosis, bruising, bleeding, erythema, oedema, necrosis, ulceration, swelling and/or inflammation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. patent applicationSer. No. 13/322,803 filed Feb. 7, 2012, which is a national stageapplication under 35 U.S.C. §371 of PCT Application No.PCT/EP2010/057493, filed May 28, 2010, which claims priority to and thebenefit of U.S. provisional patent application Ser. No. 61/213,322,filed May 29, 2009, each of which is incorporated herein by reference inits entirety.

FIELD OF THE INVENTION

The present invention is in the surgical and dermatological domain.

The present invention relates to an injectable composition comprising anadrenergic receptor agonist, preferably brimonidine, and a filler,preferably hyaluronic acid. It concerns its use in preventing and/ortreating superficial bruising and bleeding caused by aestheticprocedures.

BACKGROUND OF THE INVENTION

Superficial bruising and, to a lesser extent, bleeding are not uncommonconsequences—reported on average about one-third of the time—of manyaesthetic procedures, including dermal fillers, botulinum toxins andlaser resurfacing.

More significant bruising occurs with surgical procedures such asliposuction, breast augmentations/lifts, face lifts and tummy tucks.

The management of secondary immediate reactions due to subcutaneous orintradermal injection of fillers with vascular damages or vascularbreaking wall inducing ecchymosis, bruising, leakage of blood componentshaving immediate action on inflammation setting up, redness and oedema,are of particular interest.

Although redness, erythema, bruising and bleeding are not generallyconsidered as a big problem, most physicians prepare their patients forthis possibility by alerting them to it prior to the procedure.Particularly, physicians often caution against using aspirin or otheranticoagulant drugs before and after the procedure, extensively use icepacks immediately after the procedure and quite commonly recommendArnica, an herb used to promote healing. This kind of drawbacks maydiscourage some patients and particularly towards aesthetic procedures.In particular with regards to the consequences of bruising/bleeding,physicians report that one of the most significant concerns for patientsis downtime as when bruising occurs, patients prefer to stay home ratherthan return to work and social activities

Therefore, there is a need for alleviating bruising/bleeding that occurduring aesthetic or surgical procedures, especially when fillers areinjected.

The present invention is based on the demonstration by the Applicantthat the injection of an adrenergic receptor agonist together with thefiller reduces the occurrence of skin reactions due to injection.

DESCRIPTION OF THE INVENTION

The present invention provides a combination of quantity of adrenergicreceptor agonist, and preferably product known as brimonidine, withfillers or botulinum toxins, and preferably with hyaluronic acid. Saidcombination is systemically administrated to an individual in need.

The present invention provides the use in an individual in need, of aquantity of adrenergic receptor agonist, and preferably product known asbrimonidine, in combination with botulinum toxins or fillers, andpreferably with hyaluronic acid.

The present invention provides a method for diminishing or decreasing oravoiding bruising and, to a lesser extent, bleeding and particularly inaesthetic procedures, including dermal fillers and preferably hyaluronicacid, by providing to an individual in need thereof a quantity ofadrenergic receptor agonist, and preferably product known asbrimonidine.

In a first aspect, the invention concerns a composition comprising:

-   -   a filler or a botulinum toxin;    -   an adrenergic receptor agonist.

As it clearly appears from the present description, the presentinvention concerns the prevention and the treatment of skin defects,especially those due to skin aging (folds, wrinkles, skin depressions, .. . ) or skin damages (scars, . . . ).

Over the last years, the treatment of skin defects has become of greatinterest. As a result, it has been proposed to intradermally orsubcutaneously inject compounds.

As a first possibility, botulinum toxins which are able to provokemuscle paralysis or contraction can be locally injected.

Alternatively and in a preferred embodiment, a filler can be injected. Afiller is generally defined as a biomaterial able to fill dermaltissues. The claimed composition to be injected, comprising said fillerin an aqueous medium and displaying filling properties, can also bedefined as a “dermal filler”.

In this context, same compounds like polyacrylamid gels,polymethylmethacrylate (PMMA) particles or silicones can be used.

The most preferred compounds are resorbable molecules such as hyaluronicacid, collagen, alginate, dextran, elastine or polyurethane gels.

Hyaluronic acid or hyaluronate is a non-sulfated glycosaminoglycanwidely distributed throughout connective, epithelial, and neuraltissues. It is one of the chief components of the extracellular matrix.It contributes significantly to cell proliferation and migration. Itplays an important role in skin hydration and skin elasticity. The levelof hyaluronic acid decreases with ageing both in quantity and quality,inducing skin drying and wrinkles.

Hyaluronic acid is a naturally occurring biopolymer that forms highlyviscous solutions in water. Therefore, it is widely used as apharmaceutical product. Moreover, this compound is considered to be verysafe since no immunogenicity reaction has been observed. So far, fewminor adverse events have been noticed.

Therefore and advantageously, the filler is hyaluronic acid or apharmaceutically acceptable salt or derivative thereof, particularly thesodium or potassium salt. Hyaluronic acid can be used under differentforms: salts thereof, derivatives thereof such as esters or amides, in alinear form or cross-linked. In particular, the molecular weight,typically comprised between 500 kDa and 5 000 kDa, and the degree ofcross-linking depends on the application, especially on the depth of thewrinkles to be filled.

The second component of the claimed composition is an adrenergicreceptor agonist. Adrenergic receptor agonists are known to bind andactivate the adrenergic receptors.

As it is well known in the art, adrenergic receptors encompass both αand β receptors. Among α adrenoreceptors, α1 and α2 receptors weredistinguished in the 1970's. During the same decade, α2 receptors werefound to occur on vascular smooth muscles and exhibit mediation ofvasoconstrictor response (“Subtypes of functional α ₁- and α₂-adrenoceptors” J R Docherty; European Journal of Pharmacology 361(1998) 1-15). Thus, molecules exhibiting α adrenergic agonism,advantageously α2 adrenergic agonism, possess peripheralvasoconstrictive activity.

Agonists to be used in the claimed composition can be directed to αand/or β receptors. However, because of their possible side-effects,molecules exhibiting β adrenergic agonism, are advantageouslydisclaimed. In the rest of the application, a molecule having noaffinity for the β adrenergic receptors will be named “an α-adrenergicreceptor agonist”.

Among the α receptors, the agonist can be an agonist of both α1 and α2receptors, or can be specific for α1 or α2. Preferably, the chosenmolecule displays more affinity for the α2 than for the α1 receptor, andwill generally be named, in the rest of the application, “an α2adrenergic receptor agonist”.

In a preferred embodiment, the adrenergic receptor agonist is anadrenergic receptor agonist α2, preferably brimonidine.

Agonists of the α2 adrenoceptors have been used therapeutically for anumber of conditions including hypertension, congestive heart failure,angina pectoris, spasticity, glaucoma, diarrhea, and for the suppressionof opiate withdrawal symptoms (J. P. Heible and R. R. RuffoloTherapeutic Applications of Agents Interacting with a-Adrenoceptors, p.180-206 in Progress in Basic and Clinical Pharmacology Vol. 8, P. Lomaxand E. S. Vesell Ed., Karger, 1991).

Adrenoceptor agonists such as clonidine have been primarily used orally,though a patch formulation is known. The α2 agonists are known tomediate vasoconstriction both in the core and periphery of a patient. Inparticular α2 adrenoceptor agonists are known to cause vasoconstrictionof peripheral arterioles, in response to stimulation due to cold orstress.

A number of patents describe the use of brimonidine for treatingophthalmic conditions and eye diseases. In Canadian patent No.CA2326690, there is described the use of topical ophthalmic preparationsfor use only in the eyes, to treat eye diseases.

As already said above, the most preferred compound in the context of theinvention is(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine (commonlyreferred to as brimonidine) and pharmaceutically acceptable saltsthereof, particularly the tartrate salt.

Other compounds known to be α2 adrenoceptor agonists and which can beused in the frame of the present invention are: clonidine, apoclonidine.

More generally, other compounds which are α adrenoceptor agonists are:synephrine, octodrine, vasopressine and analogs, ornipressine,midodrine, phenylephrine, xylometazoline, oxymetazoline, norepinephrine,methoxamine.

Compounds which have also an affinity for the β receptors but which canbe used in certain conditions are: epinephrine, ephedrine, etilefrine.

Of course, the pharmaceutically acceptable salts of all these compoundsare also encompassed.

According to the instant invention, the term “pharmaceuticallyacceptable salt (s)”, as used herein, means those salts of compounds ofthe invention that are safe and effective for topical use in mammals andthat possess the desired biological activity. Pharmaceuticallyacceptable salts include salts of acidic or basic groups present in thecompounds of the invention.

Pharmaceutically acceptable acid salts include, but are not limited to,hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate,citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzensulfonate, p-toluenesulfonate and pamoate (i. e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds ofthe invention can form pharmaceutically acceptable salts with variousamino acids.

Suitable base salts include, but are not limited to, aluminum, calcium,lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.For a review on pharmaceutically acceptable salts see BERGE ET AL., 66J. PHARM. Sci. 1-19 (1977).

According to a first embodiment, the claimed composition only contains afiller, or a mixture thereof, and an adrenergic receptor agonist, or amixture thereof, advantageously hyaluronic acid and brimonidine.

According to an alternative embodiment, the claimed composition alsocontains one or more additional ingredients.

The one or more other ingredients can be active ingredients, e. g. ananaesthetic. A preferred anaesthetic is lidocaine or a pharmaceuticallyacceptable salt thereof. Other active ingredients are for example growthfactors, peptides, . . . .

The claimed composition can also contain other pharmaceutical acceptableingredients such as carriers, excipients, preservatives, . . . .

In one embodiment, the compounds of the invention are administrated to apatient in need thereof by systemic route, preferably by injection.Therefore, in the context of the instant invention the compounds aredelivered to the affected area of the skin in a pharmaceuticallyacceptable carrier. As used herein, a pharmaceutically acceptablecarrier is any pharmaceutically acceptable formulation that can beapplied to the skin for dermal, intradermal, or transdermal delivery ofa pharmaceutical or medicament. The combination of a pharmaceuticallyacceptable carrier and a compound of the invention is termed aninjectable formulation of the invention.

In the frame of the present invention, the composition is apharmaceutically acceptable injectable formulation. By “pharmaceuticallyacceptable injectable formulation” it is meant in the context of theinvention any formulation which is pharmaceutically acceptable forsystemic delivery. Preferably, the composition is administrated in thesuperficial, middle or deep dermis, by subcutaneous or intradermalroute. Typically, the claimed composition consists in a solution or agel, preferably an aqueous solution or gel.

The claimed composition is composed of or contains therapeuticallyeffective amounts of adrenergic receptor agonists and fillers. As usedherein, a “therapeutically effective amount of a compound of theinvention” means the minimum amount of the compound that is effective toobtain the desired effect in the context of the invention.

Typically, the claimed composition contains:

-   -   a filler, preferably HA, representing 1% to 2.5% by weight of        the composition;    -   an adrenergic receptor agonist, preferably brimonidine,        representing 0.0001% to 1% by weight of the composition;    -   optionally an anaesthetic, representing 0.01% to 3% by weight of        the composition

As already said, the claimed composition is meant to be administered toa subject or a patient, especially by facial injection (forehead, eyes,nasolabial fold, . . . ). As used herein, the term “subject” or“patient” are used equivalently and means any animal, preferably amammal, more preferably, a human to whom will be or has beenadministered compounds or formulations of the invention. The term“mammals” used herein encompasses any mammal.

Therefore, the invention also provides formulations to deliver asystemic dose of the compound to the patient. In practice and for atreatment sequence, the amounts of active compounds are as follows:

-   -   for the filler, preferably HA: between 0.05 mg/kg and 2 mg/kg of        body weight. It represents from 5 mg to 100 mg.    -   for the adrenergic receptor agonist, preferably brimonidine:        between 5·10⁻³ μg and 0.8 mg/kg of body weight. It represents        from 0.5 μg to 40 mg.

In a preferred embodiment, the volume of the claimed composition to beinjected varies between 0.1 and 10 ml, typically between 0.5 and 4 ml.Preferably, said volume is presented as a single dose syringe. Saidinjection can be repeated, for example after 4 to 18 months.

Another aspect of the invention is an article of manufacture thatcomprises a systemic formulation of the invention in a suitablecontainer with labelling and instructions for use. The container isadvantageously a single dose syringe.

Preferably, instructions are packaged with the formulations of theinvention, for example, a pamphlet or package label. The labellinginstructions explain how to administer formulations of the invention, inan amount and for a period of time sufficient to treat the patient.Preferably, the label includes the dosage and administrationinstructions, the formulation's composition, the clinical pharmacology,drug resistance, pharmacokinetics, absorption, bioavailability, andcontraindications.

The claimed injectable composition can then be integrated into a kitcomprising syringes containing said composition. In said kit, the twoactive principles, i. e. the filler and the adrenergic receptor agonist,can be presented as a mixture contained in a syringe or can be containedin two separate syringes for extemporaneous mixture.

The claimed composition is advantageously sterilized in conditionssuitable for preserving the active principles.

As already said, the claimed composition is dedicated to the preventionand/or treatment of skin defects, especially folds, wrinkles, skindepressions and scars. It concerns a cosmetic or a therapeutictreatment.

According to the invention, it has been shown that the main benefit ofthe claimed combination is to diminish, decrease or avoid erythema,ecchymosis, bruising or bleeding, especially in connection with theinjection of a dermal filler.

Other potential benefits of the claimed composition are as follows:

-   -   When the composition further contains an anaesthetic, e.g.        lidocaine, the efficiency of said anaesthetic is improved:        vasoconstrictive effect provided by the α adrenergic agonist        limits anaesthetic diffusion in a large area, thus making        anaesthetic efficient in the strict injection site;    -   By reducing the inflammation, the filler persists longer,        possibly due to its slower degradation: the more inflammatory        the filler is, the more tissue reaction is severe and higher is        the level of inflammatory species, thus degrading faster the        filler. Introducing a vasoconstrictive molecule in the filler        could limit inflammatory species attraction to the injection        site;    -   A reduction of oedema and swelling is observed: for the same        reason as the previous benefit, vasoconstrictive activity of the        filler limits liquid flood in reaction to the injection, so        hindering liquid concentration nearby the injection site.

More generally, the claimed composition is then intended to diminish,decrease or avoid all the undesirable skin reactions (immediate and/orsecondary) due to injection. It indeed includes ecchymosis, bruising orbleeding but also possibly redness, erythema, oedema, necrosis,ulceration, swelling and inflammation.

The claimed composition containing the two active principles can be usedsimultaneously, separately or sequentially. In other words, the presentinvention provides a kit of part combining a quantity of adrenergicreceptor agonist, and preferably product known as brimonidine, withfillers, and preferably with hyaluronic acid.

In addition to the above, the following examples are provided toillustrate particular embodiments and not to limit the scope of theinvention.

Examples

LEGENDS TO FIGURES

FIG. 1 shows the Irritating Primary Index (IPI) evolution between Day 0and Day 8 for the claimed composition (Test2) in comparison with afiller alone (Test1).

FIG. 2 shows the total score of inflammatory reaction at Day 8 for theclaimed composition (Test2) in comparison with a filler alone (Test1).

SUMMARY OF THE STUDY

An intracutaneous test of a hyaluronic acid-based dermal fillercontaining lidocaine and a vasoconstrictor drug (Brimonidine) namedRADACT014 was performed in order to evaluate the potential ofBrimonidine to reduce the irritation following intradermal injection offiller in the rabbit.

Two adult rabbits received by intracutaneous route 0.2 mL of testproduct RADACT014 (Test2), NaCl 0.9% (Test5: negative control) and10LDEEP010 (same hyaluronic acid filler as RADACT014 but with nolidocaine nor Brimonidine; Test1: positive control).

The results obtained with the filler containing Brimonidine (batchRADACT014 (Test2)) are compared with the dermal filler withoutBrimonidine (positive control: Test 1).

The sites were examined from Day 0 to Day 8 after injection for grossevidence of tissue reaction, such as erythema, oedema and necrosis(FIG. 1) and the observation of microscopic tissue response done onhistological observations after sacrifice at Day 8 (FIG. 2).

The study was conducted according to the requirements of the ISO 10993standard: Biological Evaluation of medical devices, Part 10: Test forirritation and delayed type hypersensitivity.

Materials and Methods Preparation of Control Crosslinked HyaluronicFiller: 10LDEEP010

A crosslinked hyaluronic acid filler 10LDEEP010 (Test1) was obtained bycrosslinking with 25% of BDDE a sodium hyaluronate from bacterial origincharacterized by a macromolecular weight of around 2-4×10⁶ Da. At theend of the crosslinking, a lidocaine hydrochloride was added to thecrosslinked hyaluronic acid to reach a concentration of 03%. Homogeneousblend of lidocaine is obtained by extrusion of the mix through mesh. Theresulting gel was packed in 1 mL syringes at the concentration of 20mg/mL and steam sterilized.

Preparation of Crosslinked Hyaluronic Filler Containing Brimonidine:RADACT014

The same crosslinking conditions were applied to the same hyaluronicacid to obtain a filler without lidocaine. In parallel, a 4N sodiumhydroxide solution was prepared using 8 g of NaOH and 42 g of purifiedwater. Another solution containing brimonidine and lidocaine wasobtained by dissolution of 0.22 g of brimonidine tartrate and 0.33 g oflidocaine hydrochloride in 9.45 mL of phosphate buffer. pH was adjustedto 6 by using the NaOH solution. Then, brimonidine and lidocainesolution was filtered on 0.22 microns.

A filler containing brimonidine and lidocaine, called RADACT014 (Test2),was obtained by gently mixing 5 g of the solution containing the 2actives and 50 g of the previous crosslinked hyaluronic gel into 3steps: 5 minutes of mechanical mixing followed by 15 minutes of breakand then additional 5 minutes mixing. The resulting gel was packed in 1mL syringes and steam sterilized. The final concentration of actives wasdetermined after hyaluronidase digestion for brimonidine by HPLC-MS-MSas 0.16% and for lidocaine by HPLC as 0.29%.

Investigation of Immediate Adverse Events Reduction

The potential of irritation reduction by RADACT014 was evaluated in ananimal study conducted according to the requirements of the ISO10993-10requirements: Biological Evaluation of Medical Devices—Test forirritation and delayed type hypersensitivity.

Study Protocol

At Day 0 (D0), two adult rabbits received by intracutaneous route 0.2 mLof test products (Test1: 10LDEEP010 and Test2: RADACT014) and negativecontrol (Test5: physiological saline), injected using a 27G needle. Inthese conditions, 4 sites were injected for each product.

Then, the injected sites were examined twice a day from Day 0 to Day 8for gross evidence of tissue reaction such as erythema, oedema,ulceration and necrosis, attributing a score with the followingcriterions:

Criterion Control method Scale Formation of Visual assessment (0) noneoedema (1) slight (2) moderate (3) marked (4) severe Formation of Visualassessment (0) none erythema, (1) slight ulceration (2) moderate andnecrosis (3) marked (4) severe

At Day 8, the animals were euthanized and injection sites were collectedand fixed for histological analysis. Microscopic analyses were performedto assess the following criterions:

Control Criterion method Scale Type of cell/implant reaction,Histological Score from 0 to 4 for local tolerance: analysis eachcriterion Fibrin (0) None Necrosis (1) slight Tissue degeneration (2)moderate Granulocyte (3) marked PMN eosinophils (4) severe LymphocytesPlasmocytes Macrophages Giant cells Fibrocytes Neovessels Peri andintra-implant tissue reconstruction Degradation of the material

Results Exploitation

No oedema, nor necrosis occurred in this study. Moreover, only10LDEEP010 showed a slight and persistent ulceration from day 2 to day8.

1. IRRITATION PRIMARY INDEX (IPI)

IPI of test product is determined for each observation time in thefollowing way:

${IPI}_{Test} = {\frac{\sum\; \left( {{{oedema}\mspace{14mu} {score}} + {{erythema}\mspace{14mu} {score}}} \right)}{{Observations}\mspace{14mu} {number}} - {IPI}_{{negative}\mspace{14mu} {control}}}$

-   -   Negative control being test5: physiological saline    -   IPI_(negative control) quotes 0 for each observation time.

The results obtained are shown in FIG. 1.

10LDEEP010 (Test1) showed the highest value of irritation index duringthe experiment: the index increases between Day 0 and Day 1 and thenremains stable. This product is very irritant.

Test2 Product, called RADACT014 and containing Brimonidine, showed thelowest value of IPI: it increases between Day 0 and Day 2 and thenstabilizes to Day 7 and finally decreases at Day 8.

RADACT014 showed a reduction of inflammatory effect of the dermal fillerfrom Day 3 in a pronounced and persistent way, thus demonstrating thepositive effect of Brimonidine regarding irritation.

2. HISTOLOGICAL ANALYSIS

Total scores of inflammation were determined from histologicalobservations according to local tolerance-representative cells type andquantities.

FIG. 2 represents total score of inflammation of each product.

At Day 8, moderate (10LDEEP010) to limited (RADACT014) inflammatoryinfiltrates were noted, the main cell population being macrophages witha few eosinophils. No specific reaction was observed for the negativecontrol (physiological saline, Test5).

3. CONCLUSION

This study has shown that the dermal filler (Test1: 10LDeep010) injectedin the dermal compartment provokes some inflammatory response withslight ulceration. By incorporating an active molecule (Brimonidine) inthis kind of dermal filler (RADACT014), it is possible to reduce theinflammatory response. The gross evidence (erythema, oedema, ulcerationand necrosis) and the histological analyses demonstrate both the benefitprovided by using the Brimonidine molecule in combination with thefiller.

What is claimed is:
 1. An injectable composition for treating a skindefect comprising: i. hyaluronic acid (HA); ii. an α-adrenergic receptoragonist; and iii an anaesthetic, wherein the anaesthetic is lidocaine ora pharmaceutically acceptable salt thereof.
 2. The composition of claim1, wherein the α-adrenergic receptor agonist is an α2-adrenergicreceptor agonist.
 3. The composition of claim 2, wherein theα2-adrenergic receptor agonist is brimonidine.
 4. The composition ofclaim 1, wherein the α-adrenergic receptor agonist is brimonidine,xylometazoline, or oxymetazoline.
 5. The composition of claim 1, whereinthe HA represents 1% to 2.5% by weight of the composition.
 6. Thecomposition of claim 1 wherein the lidocaine or the pharmaceuticallyacceptable salt thereof represents 0.01% to 3% by weight of thecomposition.
 7. A kit comprising at least one syringe and thecomposition of claim
 1. 8. A method for treating a skin defectcomprising the step of injecting simultaneously an individual in needthereof with: i. hyaluronic acid (HA); ii. an α-adrenergic receptoragonist; and iii an anaesthetic, wherein the anaesthetic is lidocaine ora pharmaceutically acceptable salt thereof.
 9. The method of claim 8wherein the skin defect is a fold, wrinkle, skin depression or scar. 10.The method of claim 8, wherein the α-adrenergic receptor agonist is anα2-adrenergic receptor agonist.
 11. The method of claim 10, wherein theα2-adrenergic receptor agonist is brimonidine.
 12. The method of claim8, wherein the α-adrenergic receptor agonist is brimonidine,xylometazoline, or oxymetazoline.
 13. A method for diminishing,decreasing or avoiding a skin reaction in an individual due to injectionof a dermal filler, comprising the step of injecting simultaneously: i.hyaluronic acid (HA); ii. an α-adrenergic receptor agonist; and iii ananaesthetic, wherein the anaesthetic is lidocaine or a pharmaceuticallyacceptable salt thereof.
 14. The method of claim 13 wherein the skinreaction due to injection is redness, ecchymosis, bruising, bleeding,erythema, oedema, necrosis, ulceration, swelling and/or inflammation.15. The method of claim 13, wherein the α-adrenergic receptor agonist isan α2-adrenergic receptor agonist.
 16. The method of claim 15, whereinthe α2-adrenergic receptor agonist is brimonidine.
 17. The method ofclaim 13, wherein the α-adrenergic receptor agonist is brimonidine,xylometazoline, or oxymetazoline.
 18. An injectable composition fortreating a skin defect comprising: i. a botulinum toxin; ii. anα-adrenergic receptor agonist; and iii an anaesthetic, wherein theanaesthetic is lidocaine or a pharmaceutically acceptable salt thereof.19. The composition of claim 18, wherein the α-adrenergic receptoragonist is an α2-adrenergic receptor agonist.
 20. The composition ofclaim 19, wherein the α2-adrenergic receptor agonist is brimonidine. 21.The composition of claim 18, wherein the α-adrenergic receptor agonistis brimonidine, xylometazoline, or oxymetazoline.
 22. The composition ofclaim 18 wherein the lidocaine or the pharmaceutically acceptable saltthereof represents 0.01% to 3% by weight of the composition.
 23. A kitcomprising at least one syringe and the composition of claim
 18. 24. Amethod for treating a skin defect comprising the step of injectingsimultaneously an individual in need thereof with: i. a botulinum toxin;ii. an α-adrenergic receptor agonist; and iii an anaesthetic, whereinthe anaesthetic is lidocaine or a pharmaceutically acceptable saltthereof.
 25. The method of claim 24 wherein the skin defect is a fold,wrinkle, skin depression or scar.
 26. The method of claim 24, whereinthe α-adrenergic receptor agonist is an α2-adrenergic receptor agonist.27. The method of claim 26, wherein the α2-adrenergic receptor agonistis brimonidine.
 28. The method of claim 24, wherein the α-adrenergicreceptor agonist is brimonidine, xylometazoline, or oxymetazoline.
 29. Amethod for diminishing, decreasing or avoiding a skin reaction in anindividual due to injection of a dermal filler, comprising the step ofinjecting simultaneously: i. a botulinum toxin; ii. an α-adrenergicreceptor agonist; and iii an anaesthetic, wherein the anaesthetic islidocaine or a pharmaceutically acceptable salt thereof.
 30. The methodof claim 29 wherein the skin reaction due to injection is redness,ecchymosis, bruising, bleeding, erythema, oedema, necrosis, ulceration,swelling and/or inflammation.
 31. The method of claim 29, wherein theα-adrenergic receptor agonist is an α2-adrenergic receptor agonist. 32.The method of claim 31, wherein the α2-adrenergic receptor agonist isbrimonidine.
 33. The method of claim 29, wherein the α-adrenergicreceptor agonist is brimonidine, xylometazoline, or oxymetazoline.